Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands.
Curr Opin Lipidol. 2019 Jun;30(3):205-211. doi: 10.1097/MOL.0000000000000600.
The angiopoietin-like proteins (ANGPTLs), consisting of ANGPTL3, ANGPTL4, and ANGPTL8, have gained significant interest for their role as inhibitors of lipoprotein lipase (LPL) and for their potential as therapeutic targets for correcting dyslipidemia. This review provides an overview of the most relevant new insights on the connection between ANGPTLs, plasma lipids, and coronary artery disease.
Carriers of loss-of-function variants in ANGPTL3 have a reduced risk of coronary artery disease and reduced plasma levels of triglycerides and LDL-C, while carriers of loss-of-function variants in ANGPTL4 have a reduced risk of coronary artery disease and reduced plasma levels of triglycerides and increased HDL-C. There is evidence that carrier status of ANGPTL4 loss-of-function variants may also influence risk of type 2 diabetes. ANGPTL3 is produced in liver and is released as a complex with ANGPTL8 to suppress LPL activity in fat and muscle tissue. ANGPTL4 is produced by numerous tissues and likely mainly functions as a locally released LPL inhibitor. Both proteins inactivate LPL by catalyzing the unfolding of the hydrolase domain in LPL and by promoting the cleavage of LPL. Antisense oligonucleotide and monoclonal antibody-based inactivation of ANGPTL3 reduce plasma triglyceride and LDL-C levels in human volunteers and suppress atherosclerosis in mouse models.
ANGPTL3/ANGPTL8 and ANGPTL4 together assure the appropriate distribution of plasma triglycerides across tissues during different physiological conditions. Large-scale genetic studies provide strong rationale for continued research efforts to pharmacologically inactivate ANGPTL3 and possibly ANGPTL4 to reduce plasma lipids and coronary artery disease risk.
血管生成素样蛋白（ANGPTLs）包括 ANGPTL3、ANGPTL4 和 ANGPTL8，因其作为脂蛋白脂肪酶（LPL）抑制剂的作用以及作为纠正血脂异常的治疗靶点的潜力而受到广泛关注。本文综述了 ANGPLs、血浆脂质与冠状动脉疾病之间关联的最新研究进展。
ANGPTL3 功能丧失变异的携带者患冠状动脉疾病的风险降低，血浆甘油三酯和 LDL-C 水平降低，而 ANGPTL4 功能丧失变异的携带者患冠状动脉疾病的风险降低，血浆甘油三酯水平降低，HDL-C 水平升高。有证据表明，ANGPTL4 功能丧失变异的携带者状态也可能影响 2 型糖尿病的风险。ANGPTL3 在肝脏中产生，与 ANGPTL8 形成复合物，抑制脂肪和肌肉组织中的 LPL 活性。ANGPTL4 由多种组织产生，可能主要作为局部释放的 LPL 抑制剂发挥作用。这两种蛋白通过催化 LPL 水解酶结构域的展开和促进 LPL 的裂解来使 LPL 失活。反义寡核苷酸和单克隆抗体使 ANGPTL3 失活可降低人类志愿者的血浆甘油三酯和 LDL-C 水平，并抑制小鼠模型中的动脉粥样硬化。
ANGPTL3/ANGPTL8 和 ANGPTL4 共同确保了不同生理条件下血浆甘油三酯在组织间的适当分布。大规模的遗传研究为进一步研究努力提供了强有力的依据，即通过药理学方法使 ANGPTL3 和可能的 ANGPTL4 失活，以降低血浆脂质和冠状动脉疾病风险。
